TNF signaling drives myeloid-derived suppressor cell accumulation

TNF, an inflammatory cytokine that is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. We previously reported that tumors implanted in TNF receptor-deficient (Tnfr-/-) mice are spontaneously rejected; however, the molecular mechanism...

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Veröffentlicht in:	The Journal of clinical investigation Jg. 122; H. 11; S. 4094 - 4104
Hauptverfasser:	Zhao, Xueqiang, Rong, Lijie, Zhao, Xiaopu, Li, Xiao, Liu, Xiaoman, Deng, Jingjing, Wu, Hao, Xu, Xia, Erben, Ulrike, Wu, Peihua, Syrbe, Uta, Sieper, Joachim, Qin, Zhihai
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 01.11.2012
Schlagworte:	Animals Apoptosis Biomedical research Cancer CASP8 and FADD-Like Apoptosis Regulating Protein - biosynthesis CASP8 and FADD-Like Apoptosis Regulating Protein - genetics CASP8 and FADD-Like Apoptosis Regulating Protein - immunology Caspase 8 - genetics Caspase 8 - immunology Caspase 8 - metabolism Cell Line, Tumor Cellular signal transduction Cytotoxicity Dendritic cells Gene expression Genetic aspects Graft Rejection - genetics Graft Rejection - immunology Graft Rejection - metabolism Graft Rejection - pathology Inflammation Mice Mice, Inbred BALB C Mice, Knockout Myeloid Cells - immunology Myeloid Cells - metabolism Myeloid Cells - pathology Neoplasm Transplantation Neoplasms - genetics Neoplasms - immunology Neoplasms - metabolism Neoplasms - pathology Properties Receptors, Tumor Necrosis Factor, Type I - genetics Receptors, Tumor Necrosis Factor, Type I - immunology Receptors, Tumor Necrosis Factor, Type I - metabolism Receptors, Tumor Necrosis Factor, Type II - genetics Receptors, Tumor Necrosis Factor, Type II - immunology Receptors, Tumor Necrosis Factor, Type II - metabolism Signal Transduction - genetics Signal Transduction - immunology T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes - pathology Tumor Escape Tumor necrosis factor Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - immunology Tumor Necrosis Factor-alpha - metabolism Tumors China
ISSN:	0021-9738, 1558-8238, 1558-8238
Online-Zugang:	Volltext
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Zusammenfassung:	TNF, an inflammatory cytokine that is enriched in the tumor microenvironment, promotes tumor growth and subverts innate immune responses to cancer cells. We previously reported that tumors implanted in TNF receptor-deficient (Tnfr-/-) mice are spontaneously rejected; however, the molecular mechanisms underlying this rejection are unclear. Here we report that TNF signaling drives the peripheral accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs expand extensively during inflammation and tumor progression in mice and humans and can enhance tumor growth by repressing T cell-mediated antitumor responses. Peripheral accumulation of MDSCs was drastically impaired in Tnfr-/- mice. Signaling of TNFR-2, but not TNFR-1, promoted MDSC survival through upregulation of cellular FLICE-inhibitory protein (c-FLIP) and inhibition of caspase-8 activity. Loss of TNFRs impaired the induction of MDSCs from bone marrow cells, but this could be reversed by treatment with caspase inhibitors. These results demonstrate that TNFR-2 signaling promotes MDSC survival and accumulation and helps tumor cells evade the immune system.
Bibliographie:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Authorship note: Xueqiang Zhao, Lijie Rong, and Xiaopu Zhao contributed equally to this work.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI64115